Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients. a new classification from the european society for blood and marrow transplantation

The advances in hematopoietic cell transplantation (HCT) over the last decade have led to a transplant-related mortality below 15%. Hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication of HCT that belongs to a group of diseases increasingly identified as transplant-related, systemic endothelial diseases. In most cases, SOS/VOD resolves within weeks; however, severe SOS/VOD results in multi-organ dysfunction/failure with a mortality rate >80%. A timely diagnosis of SOS/VOD is of critical importance, given the availability of therapeutic options with favorable tolerability. Current diagnostic criteria are used for adults and children. However, over the last decade it has become clear that SOS/VOD is significantly different between the age groups in terms of incidence, genetic predisposition, clinical presentation, prevention, treatment and outcome. Improved understanding of SOS/VOD and the availability of effective treatment questions the use of the Baltimore and Seattle criteria for diagnosing SOS/VOD in children. The aim of this position paper is to propose new diagnostic and severity criteria for SOS/VOD in children on behalf of the European Society for Blood and Marrow Transplantation

Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients : a new classification from the European society for blood and marrow transplantation

The advances in hematopoietic cell transplantation (HCT) over the last decade have led to a transplant-related mortality below 15%. Hepatic sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication of HCT that belongs to a group of diseases increasingly identified as transplant-related, systemic endothelial diseases. In most cases, SOS/VOD resolves within weeks; however, severe SOS/VOD results in multi-organ dysfunction/failure with a mortality rate > 80%. A timely diagnosis of SOS/VOD is of critical importance, given the availability of therapeutic options with favorable tolerability. Current diagnostic criteria are used for adults and children. However, over the last decade it has become clear that SOS/VOD is significantly different between the age groups in terms of incidence, genetic predisposition, clinical presentation, prevention, treatment and outcome. Improved understanding of SOS/VOD and the availability of effective treatment questions the use of the Baltimore and Seattle criteria for diagnosing SOS/VOD in children. The aim of this position paper is to propose new diagnostic and severity criteria for SOS/VOD in children on behalf of the European Society for Blood and Marrow Transplantation.Peer reviewe

Ultra-Structural Alterations in In Vitro Produced Four-Cell Bovine Embryos Following Controlled Slow Freezing or Vitrification

WOS: 000379423000005PubMed ID: 26293816Cryopreservation is the process of freezing and preserving cells and tissues at low temperatures. Controlled slow freezing and vitrification have successfully been used for cryopreservation of mammalian embryos. We investigated the effect of these two cryopreservation methods on in vitro produced four-cell stage bovine embryos which were classified according to their quality and separated into three groups. The first group was maintained as untreated controls (n = 350). Embryos of the second (n = 385) and the third (n = 385) groups were cryopreserved either by controlled slow freezing or by vitrification. Embryos in groups 2 and 3 were thawed after 1 day. Hundred embryos were randomly selected from the control group, and 100 morphologically intact embryos from the second and third group were thawed after 1 day and cultured to observe the development up to the blastocyst stage. The blastocyst development rate was 22% in the control group, 1% in the slow-freezing group and 3% in the vitrification group. Remaining embryos of all three groups were examined by light microscopy, transmission electron microscopy and immunofluorescence confocal microscopy with subsequent histological staining procedures. Cryopreservation caused degenerative changes at the ultra-structural level. Compared with vitrification, slow freezing caused an increased mitochondrial degeneration, cytoplasmic vacuolization, disruption of the nuclear and plasma membrane integrity, organelle disintegration, cytoskeletal damage, a reduced thickness of the zona pellucida and a formation of fractures in the zona pellucida. Further studies are required to understand and decrease the harmful effects of cryopreservation.Ege UniversityEge University [2011-Tip-064]; Ege University Local Animal Ethics Committee [2009/25]This project was supported by an Ege University Grant (2011-Tip-064), Ege University Local Animal Ethics Committee (Decision Number: 2009/25)

Aberrant O-GaINAc glycosylation to enhance AKT/mTOR signaling in pancreatic cancer.

Background: Immature truncated O-GalNAc glycosylation is an important feature of pancreatic ductal adenocarcinomas and is detected with high frequency in premalignant lesions. Differential expression of O-GalNAc glycans Tn antigen and sialyl-Tn antigen is strongly associated with decreased survival and poor prognosis and frequently occurs in pancreatic cancer due to hypermethylation of the COSMC (C1GALT1C1)gene. COSMC knockdown experiments displayed reduced rate of apoptosis and enhanced migratory behavior, thereby promoting oncogenic properties in pancreatic cancer cells. Since the underlying biological processes are not well understood, we investigated the impact of aberrant O-GalNAc glycosylation on AKT/mTOR signaling in Panc-1 and L3.6pl COSMC knockdown cells. Methods: Lentiviral mediated COSMC knockdown cell lines were subjected to stable isotope labeling by amino acids (SILAC) and subsequently analyzed by mass spectromic quantitative proteomics. Immunoprecipitation, Western blot analysis and real time PCR were used to assess glycotype dependent signaling molecule expression and phosphorylation status. Results: In COSMC knockdown cells, quantitative proteomics identified proteins associated to IGF, EGF and PI3K pathways. We could further identify AKT as novel O-GalNAc-modified protein in Panc-1 pancreatic cancer cell line. AKT downstream substrates S6 ribosomal protein and GSK-3b displayed an enhanced phosphorylation and AKT upstream effectors, such as IGF-I receptor and mTORC2 complex showed an enhanced activation in COSMC knockdown cells. Interestingly, aberrant O-glycosylation was able to modify mTOR S2448 phosphorylation in L3.6pl COSMC knockdown cells treated with mTORC inhibitor AZD8055. Conclusions: Our study revealed an enhanced AKT/mTOR signaling in pancreatic cancer COSMC knockdown cells, which is driven by aberrant O-GalNAc glycosylation and substantiates the previously observed enhancement of oncogenic properties